Salt-dependency of endothelin-induced, chronic hypertension in conscious rats.

Abstract

The effect of salt intake on the hypertensive response to long-term infusion of endothelin-1 was investigated. Chronically instrumented male Sprague-Dawley rats (325-375 g) were used in a 15-day protocol that included 3 control days followed by 7 days of endothelin-1 infusion at 5.0 pmol • kg" 1 • min" 1 and 5 days of recovery. Rats were maintained on either a normal sodium chloride intake (2.0 meq Na + per day; normal sodium) or a high sodium chloride Intake (6.0 meq Na + per day; high sodium) throughout the protocol. Control rats received normal or high sodium intakes but not endothelin-1. In high-sodium rats, endothelin-1 produced a significant increase in mean arterial pressure and total peripheral resistance; a significant bradycardia was observed only on the first day after the start of the endothelin-1 infusion. Cardiac output, stroke volume, water balance, and urinary sodium and potassium excretion remained unchanged. Termination of endothelin-1 infusion resulted in rapid normalization of both arterial pressure and peripheral resistance. In contrast, normal sodium rats exhibited no alteration in mean arterial pressure, heart rate, total peripheral resistance, stroke volume, water balance, or urinary sodium and potassium excretion throughout the endothelin-1 infusion protocol. The hypertension produced by endothelin-1 infusion cannot be explained by alterations in salt or water balance since endothelin-1 infusion in high sodium animals produced significant increases in mean arterial pressure with no observable changes in water or electrolyte balance. These results indicate that endothelin-induced hypertension in conscious rats is a salt-dependent model of hypertension. Since the isolation of ET-1 by Yanagisawa et al 1 in 1988, this 21-amino acid peptide has been shown to have both relaxing and constricting effects on vascular smooth muscle via the release of relaxing factors such as prostacyclin, 2 atrial natriuretic factor, 3 and endotheliumderived relaxing factor 2 and via the mobilization of intracellular and extracellular calcium, 4 respectively. Substantial data also exist that describe ET-1 as a constrictor of nonvascular smooth muscle, 3 a secretagogue for the release of other hormones and circulating factors such as aldosterone 67 and adrenocorticotropic hormone, 8 a suppressant of the antidiuretic action of arginine vasopressin (AVP) in the kidney, 9 a modulator of adrenergic neuroeffector transmission, 10 a potent mitogen of vascular smooth muscle cells, 11 and a regulator of neuronal activity in specific brain regions. 12In agreement with these observations, autoradiographical studies using iodine-125-labeled ET-1 have revealed that this peptide has specific high affinity binding sites within the cardiovascular system (including cardiac tissue as well as the vascularure), 13 areas within and outside of the blood-brain barrier), 1314 and the spinal cord.15 These data and others suggest that ET-1 may be involved in numerous and diverse physiological processes. However, a role for ET-1 in blo...

Endothelin-Induced Increases in Ca 2+ Entry Mechanisms of Vascular Contraction Are Enhanced During High-Salt Diet

“…Phe (10 Ϫ5 mol/L) caused an increase in 45 Ca 2ϩ influx that was greater in NS/ET (27.9Ϯ1.7) than in NS (20.1Ϯ1.8) rats and further enhanced in HS/ET (35.2Ϯ1.8) compared with HS rats (21.8Ϯ1.9 mol/kg/min). The Phe-induced 45 Ca 2ϩ influx-stress relation was not different between NS and HS rats, but was enhanced in ET-infused rats particularly those on HS. The enhancement of the 45 Ca 2ϩ influx-active stress relation in ET-infused rats was not observed in vascular strips treated with the protein kinase C inhibitor GF109203X or calphostin C (10 Ϫ6 mol/L).…”

“…The tissues were transferred to the respective radioactive 45 Ca 2ϩ labeled solution (specific activity, 2 Ci/mL; ICN) for 90 sec. Preliminary experiments have shown that the relationship between Ca 2ϩ uptake versus time is linear during 15-, 30-, 60-, and 90-second exposures to the 45 Ca 2ϩ label. The tissues were transferred to ice-cold Ca 2ϩ -free (2 mmol/L EGTA) Krebs for 45 minutes to quench extracellular 45 Ca 2ϩ label.…”

“…Preliminary experiments have shown that the relationship between Ca 2ϩ uptake versus time is linear during 15-, 30-, 60-, and 90-second exposures to the 45 Ca 2ϩ label. The tissues were transferred to ice-cold Ca 2ϩ -free (2 mmol/L EGTA) Krebs for 45 minutes to quench extracellular 45 Ca 2ϩ label. The vascular strips were weighed and placed in 2 mL hypotonic (5 mmol/L) EDTA for 24 hours at 4°C to disrupt the cell membranes and release the intracellular content of 45 Ca 2ϩ .…”

“…The tissues were transferred to ice-cold Ca 2ϩ -free (2 mmol/L EGTA) Krebs for 45 minutes to quench extracellular 45 Ca 2ϩ label. The vascular strips were weighed and placed in 2 mL hypotonic (5 mmol/L) EDTA for 24 hours at 4°C to disrupt the cell membranes and release the intracellular content of 45 Ca 2ϩ . The next day, 4 mL of Ecolite scintillation cocktail was added, and the samples were counted in a scintillation counter (Beckman LS 6500).…”

“…mol/L)-induced active stress and 45 Ca 2ϩ influx were measured at increasing concentrations of extracellular Ca 2ϩ . In all groups of rats, increasing concentrations of extracellular Ca 2ϩ were associated with increases in Phe-induced stress and 45 Ca 2ϩ influx (Figure 4).…”